This application proposes treatment of the localized nature of restenosis using the concept of local drug delivery. The investigators plan to develop drug loaded sustained release polymeric biodegradable nanoparticles that can be infused via the intra-arterial route for the inhibition of restenosis. In their initial studies, it was demonstrated that dexamethasone/nanoparticles in the rat carotid and U86983/nanoparticles in the pig coronary modes inhibit restenosis. The goals of the proposed research are to address basic questions relating to the mechanism of nanoparticles surface characteristics and intra-arterial localization and retention, release of therapeutic agents, efficacy at local dose and biocompatibility consideration. The objective will be to elucidate mechanisms and establish criteria for the effective and reliable applications of nanoparticles for the intra-arterial localization of therapeutic agents in restenosis.
The specific aims i nclude: 1) Investigation of biodegradable nanoparticles and their surface modification for efficient intra-arterial localization. 2) Characterization of nanoparticles for physico-chemical properties. 3) Evaluation of therapeutic efficacy of dexamethasone/nanoparticles in the inhibition of restenosis. Polylactic/polyglycolic acid copolymers and polycaprolactones will be used to form 100nm diameter of nanoparticles. In addition, the surface of nanoparticles will be modified and dexamethasone loaded nanoparticles will be evaluated in the pig coronary artery model of restenosis.
